Distribution, Toxicity and Mode of Action of The Novel Copper-Based Anticancer Compound: Casiopeina II.

The in vivo fate and toxicity of the novel copper-based anticancer agent casiopeina II ([Cu(4,7-dimethyl-l,10-phenanthroline)(glycine)NO3]), and in vitro mode of cell death induced in two cancer cell lines were investigated. After a single intravenous administration of 3H-casiopeina II (5mg/kg dose) in the rat the complex was rapidly distributed to tissues, the 3H-phenanthroline was excreted via urine and faeces whilst the copper appeared to be predominantly retained with a small amount being excreted via faeces. Differences in tissue copper retention and 3H-phenanthroline elimination suggest an in vivo dissociation of the complex. The major toxic effect attributed to casiopeina II administration was haemolytic anaemia (reduced haemoglobin concentration, red blood cell count and packed cell volume as well as leukocytosis and neutrophilia) observed at 12 hours and 5 days after administration can be attributable to direct erythrocyte oxidative damage. Increased reticulocyte levels and the presence of normoblasts in peripheral blood 5 days after administration indicated an effective erythropoietic response and tendency towards recovery at 15 days. Increase in spleen weight was attributed to an increased uptake of damaged erythrocytes by the reticuloendothelial system. Older rats (10-week old) appeared to be more susceptible to the haemolytic damage than younger rats (6-week old) possibly due to a reduced erythrocytic tolerance. Erythropoietin pretreament before casiopeina II administration reduced the haematological effects. Cell death by apoptosis, induced in vitro in CH1 human ovarian carcinoma and L1210 murine leukaemia cells after casiopeina II treatment, was observed by cell morphology, DNA integrity and caspase activation. Cisplatin resistant and susceptible forms of CH1 and L1210 cells were equally sensitive to casiopeina II apoptosis induction. The mechanism by which casiopeina II activates caspases in the two cell lines, although unclear, suggests an intracellular trigger such as intramitochondrial ROS generation by the Cu(II) moiety of casiopeina II